An emerging challenge for tuberculosis (TB) control is the steadily rising number of individuals with type 2 diabetes (DM2), particularly in developing countries where TB is endemic. DM2 increases the risk of TB by three fold and there are now more people affected by TB-DM co-morbidity than TB-HIV infection. A better understanding of the link between TB and DM2 is essential to identify individuals at increased risk for TB progression. In DM2 patients, the interplay of hormones under neuroendocrine regulation, adipokines and insulin, and chronic low grade inflammation are likely to contribute to compromised immune responses to Mycobacterium tuberculosis (Mtb). We propose studies in house hold contacts of TB cases (HHCs) in two populations with different background ethnicities: Coloureds in South Africa and Hispanics in Texas. We hypothesize that HHCs with latent Mtb infection and DM2 are characterised by a systemic dysregulation of immune-endocrine networks that lead to compromised immunity to Mtb. We will determine if there are unique signatures in serum cytokines and hormones as well as whole blood gene transcripts by DM2 status. This will allow us to identify relationships between immune and endocrine alterations in the blood of HHCs with DM2 (vs. no DM2) in two different ethnicities (Aim 1). To further ascertain whether these immune-endocrine relationships are associated with diminished cell activation and Mtb growth inhibitory capacity we will evaluate the impact of serum cytokines and hormones on the response of peripheral monocytes and T cells to Mtb in HHCs with and without DM2. We will evaluate monocyte and T cell activation as well as Mtb phagocytosis and growth by conducting parallel incubation of cells with autologous and heterologous sera (i.e., normal sera with DM2 cells and DM2 sera with no DM2 cells) (Aim 2). Finally, we hypothesize that human alveolar macrophages (HAMs) from HHCs with DM2 have altered cell activation and reduced capacity to contain Mtb growth. We will collect bronchoalveolar lavage from a subset of study participants and evaluate HAM phenotype, Mtb growth and cytokine production. In parallel, monocyte derived macrophages (MDMs) will be generated and evaluated to identify relationships between local and systemic immune-endocrine alterations in responses to Mtb by HAMs and MDMs. These findings will demonstrate whether information gained from the periphery correlates with immune responses at the site of infection. At study completion, we will have gained critical and fundamental new insights into the interplay between the immune and endocrine systems, both in the periphery and lung; thereby helping to identify underlying risk factors in DM2 patients for progression to active TB.